Transient Lower Esophageal Sphincter Relaxation Pharmacokinetic-Pharmacodynamic Modeling: Count Model and Repeated Time-To-Event Model

• DOI: 10.1124/jpet.111.181636
• Publication Date: 2011-09-03T02:52:41Z
• Authors: Elodie L. Plan; Guangli Ma; Mats Någård; Jörgen Jensen; Mats O. Karlsson
• Keywords: Pharmacodynamics; Esophageal sphincter

Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism for gastroesophageal reflux. Characterizations of candidate compounds reduction TLESRs are traditionally done through summary exposure and response measures would benefit from model-based analyses exposure-TLESR events relationships. Pharmacokinetic (PK)-pharmacodynamic (PD) modeling approaches treating either as count data or repeated time-to-event (RTTE) were developed compared in terms their ability to characterize system drug characteristics. Vehicle comprising 294 TLESR collected nine dogs. Compound [(<i>R</i>)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-<i>de</i>]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55212-2)] containing 66 events, well plasma concentrations, obtained four Each experiment lasted 45 min was initiated with a meal. Counts equispaced 5- 1-min intervals modeled based on Poisson probability distribution model. analyzed RTTE The PK connected PD one-compartment described by baseline surge function; peak determined be approximately 9.69 all approaches, its width time at half-maximal intensity 5 (1-min RTTE) 10 (5-min count). inhibition WIN55212-2 an <i>I</i>_max model, IC₅₀ average 2.39 nmol · l⁻¹. Modeling using linked dynamic PK-PD representation superior associated higher power detecting statistically significant effect.